BACKGROUND The aim of this study was to investigate the effects of nifedipine on the bioavailability and pharmacokinetics of repaglinide in rats. METHODS The effect of nifedipine on P-glycoprotein (P-gp) and cytochrome P450 (CYP) 3A4 activity was evaluated. The pharmacokinetic parameters of repaglinide and blood glucose concentrations were also determined in rats after oral (0.5 mg/kg) and intravenous (0.2 mg/kg) administration of repaglinide to rats in the presence and absence of nifedipine (1 and 3 mg/kg). RESULTS Administration of nifedipine resulted in inhibition CYP3A4 activity with an IC50 value of 7.8 μM, and nifedipine significantly inhibited P-gp activity in a concentration-dependent manner. Compared to the oral control group, nifedipine significantly increased the area under the plasma concentration-time curve (AUC0-∞) and the peak plasma concentration (Cmax) of repaglinide by 49.3 and 25.5%, respectively. Nifedipine significantly decreased the total body clearance (CL/F) of repaglinide by 22.0% compared to the oral control group. Nifedipine also increased the absolute bioavailability (AB) of repaglinide by 50.0% compared to the oral control group (33.6%). In addition, the relative bioavailability (RB) of repaglinide was 1.16- to 1.49-fold greater than that of the control group. Compared to the intravenous control, nifedipine significantly increased AUC0-∞ of repaglinide. Blood glucose concentrations had significant differences compared to the oral control groups. CONCLUSIONS Nifedipine enhanced the oral bioavailability of repaglinide, which may be mainly attributable to inhibition of CYP3A4-mediated metabolism of repaglinide in the small intestine and/or in the liver and to inhibition of the P-gp efflux transporter in the small intestine and/or reduction of total body clearance by nifedipine. The current study has raised awareness of potential drug interactions by concomitant use of repaglinide with nifedipine.